Allergic airway inflammation affects approximately 334 million people worldwide, including 13.6% of the population of the United States, and its rate continues to increase in both urbanized and developing countries. This disease afflicts patients of all ages and normally progresses to chronic illness. There is no cure for allergic asthma, making it one of the most expensive diseases for healthcare systems in developed countries. This makes our work highly significant. Allergic airway inflammation is characterized with elevated levels of inflammatory cytokines such as those produced by Th2 and Th17 cells, which are counter- regulated by immune cells with suppressive function. Interleukin-10 (IL-10) is an immunomodulatory cytokine with demonstrated anti-inflammatory effects. Genetic deficiency or polymorphisms resulting in the absence or reduction of IL-10 production are associated with increased risk of allergic inflammation. Both the pathogenic Th2 and Th17 can express high levels of IL-10 receptor, and IL-10 directly functions on Th2 and Th17 to limit their development and function during inflammation. To date, the only preventive therapy for allergic asthma is allergen-specific immunotherapy (allergen-SIT). The success of allergen-SIT correlates with the induction of IL- 10-producing T cells. We have found that, in various pulmonary inflammatory disease models, T cells are the major contributors to IL-10 production, mainly composed of three IL-10-producing T cell subsets: CD4+ Foxp3+ regulatory T (Treg), CD4+ Foxp3- IL-10hi type 1 regulatory T (Tr1) and CD8+ IL-10+ T cells. We induced and expanded the IL-10-producing T cells in vitro and found a profound therapeutic effect of these cells in a murine model of allergic airway inflammation. Further experiments revealed that these IL-10-producing T cells are heterogeneous, and molecular markers currently known as Tr1 cell signatures lack the ability to distinguish IL- 10-producing T cell subsets. Based on these findings, we hypothesize that molecular signatures and pathways associated with the heterogeneity of IL-10-producing therapeutic T cells can be exploited to identify and isolate therapeutic T cells, and can be manipulated to promote the development and therapeutic effect of these cells in allergic asthma. We propose experiments in three Specific Aims to determine: a) the effective components of the therapeutic T cells; b) the heterogeneity among and within IL-10- producing T cell subsets; and c) the molecular signatures of these cells and pathways that can be exploited to manipulate the development and function of therapeutic T cells in allergic asthma. This work is highly innovative as we utilize comprehensive biochemical, genetic and genomics approaches with unique transgenic mouse models, and have exciting preliminary data that can be expanded to provide information sets for a better understanding of pulmonary inflammatory disease control, as well as to help develop strategies to manipulate the development and function of IL10-producing T cells as a potential therapy against allergic airway inflammation and other related inflammatory diseases.